The papillomaviruses induce benign, proliferative squamous epithelial lesions in their natural hosts and can only undergo vegetative replication in terminally differentiated epithelial cells. This requirement has hampered the study of the complete viral life cycle because of the difficulties in generating a differentiated stratified epithelium in tissue culture. Bovine papillomavirus type 1 (BPV-1) induces benign fibropapillomas and can transform rodent cells in culture. The viral genome is maintained as an episome within transformed cells and this system has allowed extensive genetic analysis of the viral functions required for DNA replication, gene expression and transformation. Much less is known about BPV-1 gene expression and replication in bovine epithelial cells and the study of the complete viral life cycle requires a system to generate a fully differentiated stratified bovine epithelium. Using a combination of organotypic raft cultures and xenografts on nude mice we have developed a system in which we can generate fully differentiated bovine epithelium in which BPV-1 can replicate and produce infectious viral particles.